EP2240442B1 - Preparation process useful in synthesis of atorvastatin - Google Patents

Preparation process useful in synthesis of atorvastatin Download PDF

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Publication number
EP2240442B1
EP2240442B1 EP08741152A EP08741152A EP2240442B1 EP 2240442 B1 EP2240442 B1 EP 2240442B1 EP 08741152 A EP08741152 A EP 08741152A EP 08741152 A EP08741152 A EP 08741152A EP 2240442 B1 EP2240442 B1 EP 2240442B1
Authority
EP
European Patent Office
Prior art keywords
chemical formula
substituted
butyl
cis
dioxane
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP08741152A
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German (de)
English (en)
French (fr)
Other versions
EP2240442A2 (en
EP2240442A4 (en
Inventor
Dong-Ock Cho
Younja Kwon
Kyeong-Hoi Cha
Yeongsook Kim
Hyun-Seop Tae
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medichem Korea Co Ltd
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Medichem Korea Co Ltd
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Filing date
Publication date
Application filed by Medichem Korea Co Ltd filed Critical Medichem Korea Co Ltd
Priority to PL08741152T priority Critical patent/PL2240442T3/pl
Publication of EP2240442A2 publication Critical patent/EP2240442A2/en
Publication of EP2240442A4 publication Critical patent/EP2240442A4/en
Application granted granted Critical
Publication of EP2240442B1 publication Critical patent/EP2240442B1/en
Not-in-force legal-status Critical Current
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a preparation process useful in synthesis of atorvastatin, more particularly a process for preparing atorvastatin of Chemical Formula 1 below, which is effective in treating hyperlipemia, comprising protecting the dihydroxy group at C3 and C5 positions of the starting material cis - t -butyl-6-substituted-3,5-dihydroxy-hexanoate with trialkyl orthoformate, reducing the terminal nitro or cyano group to amine group, performing N -alkylation by sequentially reacting with ethyl 4-fluorobenzene-2-haloacetate and isobutyryl chloride, cyclizing with N ,3-diphenylpropynamide, and performing deprotection and hydrolysis:
  • Atorvastatin is an effective inhibitor of HMG-CoA reductase, and is thus effective in treating hyperlipemia. It has been commercially available in the name of Lipitor TM .
  • the starting material ethyl ⁇ -bromo-4-fluorobenzene acetate of Chemical Formula 12 is reacted with ethyldioxalane ethylamide to obtain the compound of Chemical Formula 13.
  • the tertiary amine compound of Chemical Formula 14 is prepared and cyclized to obtain the compound of Chemical Formula 15 with atorvastatin frame structure.
  • the compound of Chemical Formula 17 is obtained through a multi-step process consisting of at least three steps.
  • the ketone group of the compound of Chemical Formula 17 is reduced to obtain the compound of Chemical Formula 10-A with chiral cis -diol structure, and atorvastatin is obtained following several steps.
  • the improved process for preparing atorvastatin according to Scheme 2 is also industrially inapplicable, because it requires a harsh reaction condition and gives low production yield and purity.
  • Korean Patent Publication No. 2004-84915 has disclosed a compound of Chemical Formula 4-B as intermediate for synthesis of atorvastatin, which has a chemical structure relatively easy to protect and deprotect:
  • the compound of Chemical Formula 4-B When compared with the compound of Chemical Formula 4-A, in which the dihydroxy group is protected by 2,2-dimethyldioxane, the compound of Chemical Formula 4-B requires a milder condition for protection and deprotection and provides improved yield.
  • An object of the present invention is to provide a novel process for preparing atorvastatin of Chemical Formula 1, which is industrially applicable and provides the target atorvastatin compound with high yield and purity, without impurities.
  • the present invention has been made in an effort to solve the above-described problems associated with the prior art.
  • the present invention provides a process for preparing atorvastatin according to Scheme 3 below, which comprises the steps of:
  • the compounds of Chemical Formula 4, Chemical Formula 7 and Chemical Formula 9, which are obtained as reaction intermediates during the preparation process according to Scheme 3, are novel compounds.
  • the present invention provides the novel compounds of Chemical Formula 4, Chemical Formula 7 and Chemical Formula 9.
  • step i) the dihydroxy group of cis - t -butyl-6-substituted-3,5-dihydroxy-hexanoate of Chemical Formula 2 is protected.
  • the present invention is characterized in that trialkyl orthoformate of the formula CH(OR 2 ) 3 is selectively used as a protecting agent of the dihydroxy group.
  • the process of introducing the protecting group is described in more detail.
  • the dihydroxy group of cis - t -butyl-6-substituted-3,5-dihydroxy-hexanoate of Chemical Formula 2 can be protected quantitatively using trialkyl orthoformate in adequate solvent in the presence of acid catalyst, under a mild temperature condition of 0 °C to room temperature, preferably 0 to 5 °C.
  • the acid catalyst used in the protection may be selected from sulfuric acid, hydrochloric acid, acetic acid, methanesulfonic acid, camphorsulfonic acid (CSA), p -toluenesulfonic acid, etc.
  • Adequate solvent may be selected from tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diethyl ether, benzene, dichloromethane, acetonitrile, etc.
  • step ii) the terminal nitro or cyano group of the compound of Chemical Formula 3 with the dihydroxy group protected is reduced to amino group.
  • the reduction is performed by hydrogenation using mixture solvent of THF and C 1 -C 4 alcohol, in the presence of palladium catalyst and ammonia or ammonium formate. More specifically, of the compound of Chemical Formula 3 with the dihydroxy group protected is hydrogenated in mixture solvent of THF and methanol at 20 to 30 °C, in the presence of ammonia or ammonium formate and 10 %-palladium/carbon catalyst, to obtain cis - t -butyl-2-alkoxy-3,5-dioxane-7-amino-heptanoate of Chemical Formula 4.
  • step iii) the terminal amine group of the compound of Chemical Formula 4 is converted to tertiary amine group by N -alkylation.
  • Ethyl 4-fluorobenzene-2-haloacetate and isobutyryl chloride are used in the N- alkylation as alkylating agents.
  • cis - t -butyl-2-alkoxy-3,5-dioxane-6- N N -disubstituted amino-heptanoate of Chemical Formula 7 is obtained.
  • the N -alkylation is performed at 0 to 5 °C. Within 1 to 2 hours, the compound of Chemical Formula 7 can be obtained quantitatively, with high purity (95 % or better).
  • Adequate solvent may be selected from tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diethyl ether, benzene, dichloromethane, acetonitrile, etc.
  • base may be added.
  • the base may be an inorganic or organic base commonly used in the related art. Primary, secondary or tertiary organic base, e.g., C 1-10 alkylamine, pyridine, etc., is preferred.
  • step iv) the tertiary amine compound of Chemical Formula 7 is cyclized with N ,3-diphenylpropynamide.
  • the cyclization is performed in acetic acid anhydride by heating to 60 to 90 °C to obtain 5-(4-fluorophenyl)-2-(1-methylethyl)-1-( cis - t -butyl-2-alkoxy-3,5-dioxane-7-amido-heptanoate)- N ,4-diphenyl-1H-pyrrole-3-carboxamide of Chemical Formula 9.
  • step v) the cyclized compound of Chemical Formula 9 is deprotected and hydrolyzed to obtain the target compound atorvastatin of Chemical Formula 1.
  • the deprotection is performed using C 1 -C 4 alcohol and acid catalyst, under a relatively mild reaction condition of 0 °C to room temperature ( ⁇ 25 °C).
  • the acid catalyst used in the deprotection may be selected from sulfuric acid, hydrochloric acid, acetic acid, methanesulfonic acid, camphorsulfonic acid (CSA), p -toluenesulfonic acid, etc.
  • the deprotection is performed in alcohol solvent such as methanol or ethanol, and then stirring is performed in aqueous HCl solution at 0 °C to room temperature ( ⁇ 25 °C) for 1 to 1.5 hours in order to obtain the compound of Chemical Formula 10.
  • a solvent selected from water, methanol, ethanol, propanol, butanol, acetone, tetrahydrofuran (THF), dichloromethane and a combination thereof may be further used as reaction solvent for the deprotection.
  • hydrolysis may be performed consecutively. The hydrolysis is performed in aqueous solution.
  • the hydrolysis is performed by adding purified water to the solution containing the compound of Chemical Formula 10, solidifying the compound, dissolving in methanol after removing remaining acid, and consecutively adding an aqueous solution containing sodium hydroxide.
  • acid is added to the reaction solution to adjust pH to from 1 to 4, preferably from 2 to 3, to obtain the target compound atorvastatin of Chemical Formula 1.
  • the deprotection and the hydrolysis are performed consecutively.
  • the yield of the two steps is as high as 88.3 %.
  • the preparation process of the present invention provides high production yield and purity, although the process is relatively simple and the reaction condition is mild. Accordingly, the preparation process is well suited for industrial application for the production of atorvastatin, which is useful in treating hyperlipemia.
  • the target compound was obtained quantitatively in the same manner as in Example 1, except for using CH(OEt) 3 as a protecting agent.
  • 1 H NMR (CDCl 3 ) 1.0 (t, 3H), 1.28 (s, 9H), 1.4-1.6 (m, 4H), 2.23 (dd, 2H), 2.62 (t, 2H), 3.23 (t, 2H), 3.76 (m, 1H), 4.34 (m, 1H), 5.31 (s, 1H).
  • the target compound was obtained quantitatively as colorless oil in the same manner as in Example 1, except for using cis -t-butyl-6-cyano-3,5-dihydroxy-hexanoate (19.0 mmol) as a starting material.
  • 1 H NMR (CDCl 3 ) 1.29 (s, 9H), 1.4-1.6 (m, 2H), 2.2-2.7 (m, 4H), 3.18 (s, 3H), 3.76 (m, 1H), 4.34 (m, 1H), 5.30 (s, 1H).
  • the target compound was obtained quantitatively as colorless oil in the same manner as in Example 1, except for cis - t -butyl-6-cyano-3,5-dihydroxy-hexanoate (19.0 mmol) as a starting material and using CH(OEt) 3 as a protecting agent.
  • 1 H NMR (CDCl 3 ) 1.0 (t, 3H), 1.28 (s, 9H), 1.4-1.6 (m, 2H), 2.2-2.7 (m, 4H), 3.26 (t, 2H), 3.76 (m, 1H), 4.34 (m, 1H), 5.37 (s, 1H).
  • Example 2 5 g (18.2 mmol) of the cis - t -butyl-2-methoxy-3,5-dioxane-7-nitro-heptanoate obtained in Example 1 was added to a mixture solvent of 50 mL of MeOH and 50 mL of THF saturated with ammonia. Hydrogenation was performed for 6 hours at room temperature in the presence of 10 % Pd/C catalyst. 4.43 g (88.6 %) of the target compound was obtained as colorless oil.
  • the target compound was obtained (yield: 89.8 %) in the same manner as in Example 5, except for using cis - t -butyl-2-ethoxy-3,5-dioxane-7-nitro-heptanoate as a starting material.
  • 1 H NMR (CDCl 3 ) 1.0 (t, 3H), 1.28 (s, 9H), 1.4-1.6 (m, 2H), 2.2-2.7 (m, 4H), 3.26 (t, 2H), 3.76 (m, 1H), 4.34 (m, 1H), 5.30 (s, 1H).
  • reaction mixture was washed consecutively with 30 mL of 2 N-HCl and 100 mL of water, and then concentrated under reduced pressure. After dissolving the concentrate in 20 mL of MeOH, 1.5 g of NaOH dissolved in 10 mL of water was added, and stirring was performed at 0 °C for 1 hour. After concentrating under reduced pressure and adjusting pH to 2.0, the reaction solution was extracted with dichloromethane. The extract was washed with water and brine, dried with magnesium sulfate, and then concentrated to obtain 16.6 g (96.3 %) of the target compound as solid.
  • the process for preparing atorvastatin according to the present invention requires no redundant step for introducing particular functional groups. All the reactions of the 7 steps are performed under relatively mild conditions for a short time. Further, atorvastatin is obtained in high yield. Therefore, the preparation process according to the present invention is industrially applicable.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP08741152A 2008-01-02 2008-04-04 Preparation process useful in synthesis of atorvastatin Not-in-force EP2240442B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PL08741152T PL2240442T3 (pl) 2008-01-02 2008-04-04 Sposób wytwarzania przydatny w syntezie atorwastatyny

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020080000083A KR100850558B1 (ko) 2008-01-02 2008-01-02 아토르바스타틴의 효율적인 제조방법
PCT/KR2008/001902 WO2009084773A2 (en) 2008-01-02 2008-04-04 Preparation process useful in synthesis of atorvastatin

Publications (3)

Publication Number Publication Date
EP2240442A2 EP2240442A2 (en) 2010-10-20
EP2240442A4 EP2240442A4 (en) 2011-01-19
EP2240442B1 true EP2240442B1 (en) 2012-06-20

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EP08741152A Not-in-force EP2240442B1 (en) 2008-01-02 2008-04-04 Preparation process useful in synthesis of atorvastatin

Country Status (6)

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US (1) US8124790B2 (pl)
EP (1) EP2240442B1 (pl)
JP (1) JP2011515328A (pl)
KR (1) KR100850558B1 (pl)
PL (1) PL2240442T3 (pl)
WO (1) WO2009084773A2 (pl)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112851504B (zh) * 2021-02-09 2022-10-14 山东艾孚特科技有限公司 一种异丁酰乙酸甲酯的合成方法

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4681893A (en) * 1986-05-30 1987-07-21 Warner-Lambert Company Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis
US5003080A (en) * 1988-02-22 1991-03-26 Warner-Lambert Company Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis
US5216174A (en) * 1988-02-22 1993-06-01 Warner-Lambert Co. Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5124482A (en) * 1988-02-22 1992-06-23 Warner-Lambert Company Process for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis
FI94339C (fi) * 1989-07-21 1995-08-25 Warner Lambert Co Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
WO1998004543A1 (en) 1996-07-29 1998-02-05 Warner-Lambert Company Improved process for the synthesis of protected esters of (s)-3,4-dihydroxybutyric acid
WO2002057229A1 (en) * 2001-01-19 2002-07-25 Biocon India Limited FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN)
EP1480943A2 (en) 2002-11-15 2004-12-01 Teva Pharmaceutical Industries Limited Synthesis of 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acids
AU2004317570B2 (en) * 2004-03-17 2011-01-06 Ranbaxy Laboratories Limited Process for the production of atorvastatin calcium in amorphous form
CN1980890A (zh) * 2004-05-31 2007-06-13 兰贝克赛实验室有限公司 阿托伐他汀的制备方法
WO2006110918A1 (en) 2005-04-13 2006-10-19 Ambit Biosciences Corporation Pyrrole compounds and uses thereof
ATE432276T1 (de) 2005-09-09 2009-06-15 Pfizer Science & Tech Ltd Herstellung eines atorvastatin-zwischenprodukts
KR20080000083A (ko) * 2006-06-26 2008-01-02 엘지.필립스 엘시디 주식회사 액정표시소자의 제조방법

Also Published As

Publication number Publication date
WO2009084773A2 (en) 2009-07-09
PL2240442T3 (pl) 2012-11-30
WO2009084773A3 (en) 2010-02-18
US20110112309A1 (en) 2011-05-12
KR100850558B1 (ko) 2008-08-06
EP2240442A2 (en) 2010-10-20
JP2011515328A (ja) 2011-05-19
US8124790B2 (en) 2012-02-28
EP2240442A4 (en) 2011-01-19

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